Project Summary Alzheimer?s disease (AD)-related brain changes are detectable with neuroimaging years before symptom onset,1 and should be targeted for intervention before irreversible pathological damage occurs. These early features that precede cognitive decline include reduced cerebral blood flow2 and brain glucose metabolism.1,3,4 Maintaining adequate Vascular Endothelial Growth Factor (VEGF) function is critical, to combat these reductions and resist neurodegeneration.5-9 VEGF is upregulated as a positive repair mechanism to these reductions, helping to resupply oxygen and glucose to nutrient-deficient tissue.10 VEGF exerts neuroprotective effects by regulating angiogenesis,11,12 neurogenesis,13,14 glucose transport,15 and inhibiting cell-death pathways.10 Importantly, VEGF can be upregulated through both endogenous and exogenous mechanisms,14,16,17 making it a viable therapeutic target. VEGF?s therapeutic efficacy is clear in animal models, where it reduces amyloid deposition and improves cognitive function.14,18-22 Some human studies show similar results, with elevated VEGF levels associated with better aging outcomes, such as less hippocampal atrophy and better cognitive function.23,24 However, other human studies report that AD patients have elevated cerebrospinal fluid (CSF) VEGF levels compared with controls.25,26 We propose that the variability in human studies may be a result of each subject having differing biological (bio)-stressor levels that interfere with VEGF?s upregulation ability. For example, inflammation,7 atherosclerosis,27-29 and amyloid plaques9 are AD-relevant bio-stressors known to modify VEGF signaling. We will address this by assessing whether CSF VEGF?s effect on cognition and AD brain biomarkers is modified by three VEGF-interfering bio-stressors: 1) inflammation, measured by plasma tumor necrosis factor alpha (TNFa);9 2) atherosclerosis,30,31 reflected here by an associated measure, heart-type fatty acid binding protein (H-FABP),32 and 3) amyloid deposition, indexed by CSF amyloid-b1-42 (Ab). Our study will evaluate 310 Alzheimer?s Disease Neuroimaging Initiative (ADNI) participants across diagnostic groups (AD, mild cognitive impairment, and cognitively intact controls), aged 55 to 90 years old. Aim 1: We will evaluate for the first time in humans whether these interfering bio-stressors (inflammation, atherosclerosis, and Ab deposition) modulate CSF VEGF?s effect on cognition (executive function and memory processing). Aim 2: We will assess whether these bio-stressors interact with CSF VEGF to influence AD neuroimaging biomarkers: hippocampal volume, cortical thickness, white matter hyperintensities (WMH), and regional cerebral glucose metabolism (measured by [18F]fluorodeoxyglucose (FDG) PET). Aim 3: We will evaluate possible mediating factors, through structural equation modeling (SEM), to help explain the previously reported effect between CSF VEGF and cognition.23 Overall, we will gain insights that focus future research on interventions that target direct and indirect repair mechanisms that are disrupted in AD pathogenesis. !